Project Summary/Abstract Patients with severe burn injuries endure profound loss of skeletal muscle (SM) and adipose tissue (AT) mass and function, which is thought to contribute to systemic insulin resistance (IR) to glucose disposal, a condition that persists long after the acute event. These abnormalities increase the risk for metabolic complications including metabolic syndrome (MS), type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD). The overall objective of Project 9 is to restore metabolic function in burn patients and better understand the mechanisms underlying muscle and fat catabolism and IR in burn survivors. We will study the compartmental effects of oxandrolone (OX) treatment on short-term (acute phase) and long-term (1 year post- injury) SM protein synthesis and breakdown, and the impact this has on SM mass and quality. We will also study the effects of OX on AT mass and fat distribution, and whole-body lipid and glucose metabolism. In all cases the use of OX will be compared to that of our standard of care (SOC), which includes use of the non- selective ?-blocker propranolol. The central hypothesis for this project is that SOC + OX will increase muscle mass and triglyceride (TG) storage in subcutaneous AT; decrease intrahepatic (IH) TG content, gluconeogenesis and IR; and so improve overall glucose homeostasis. This hypothesis will be tested by pursuing three specific aims, to: AIM 1: (1.1): Determine the impact of OX treatment on muscle protein turnover in critical cellular compartments, testing the hypothesis that OX stimulates protein accretion in myofibrillar and mitochondrial (Mito) protein pools, thereby blunting protein wasting and deconditioning in burn survivors; (1.2): Determine the impact of OX treatment on muscle contractile fiber composition and oxidative capacity, testing the hypothesis that OX will blunt the loss of both myofibrillar (contractile) and Mito proteins, thus maintaining better muscle contractile and bio-energetic capacity. (1.3): Identify the key molecular pathways altered by OX treatment in burn victims, testing the hypothesis that OX will significantly blunt proteasome- and Mito- mediated protein breakdown in burn victims and stimulate muscle satellite cell proliferation, thereby promoting muscle regeneration after burns. AIM 2: Determine the effect of OX treatment on fat distribution and AT lipid metabolism, testing the hypothesis that OX stimulates TG synthesis and fat deposition in the subcutaneous AT compartment, thereby blunting lipolysis and ectopic TG deposition in the livers of burn survivors. AIM 3: Determine the effect of OX treatment on glucose metabolism, testing the hypothesis that OX decreases the hepatic glucose output (HGO) of burn survivors by affecting all pathways involved in HGO (from glycogen, glycerol and the citric acid cycle), but particularly gluconeogenesis from glycerol and the citric acid cycle. We also hypothesize that OX improves peripheral glucose disposal and ?-cell function, thus increasing the disposition index.